CCl4 intoxication in rats results in a loss of hepatic mitochondrial structure and function, as indicated by low rates of coupled respiration in isolated mitochondria, swollen ultrastructural appearance, and a decline of cellular ATP levels. Administration of chloramphenicol (chloromycetin: (CAP) simultaneously with CCl4 results in little disruption of mitochondrial function or morphology, maintenance of cellular ATP concentrations, and an increase of the LD50 of CCl4. An investigation of the protective mechanism was proposed that would use the optical isomer of CAP (L-CAP) and a sulfamyl derivative, Tevenel, to establish the mechanism of protection. Results of the first year's work have established that Tevenel (which, like CAP, inhibits mitochondrial protein synthesis) fails to protect, while L-CAP (inactive on mitochondrial protein synthesis) does protect. Having ruled out the involvement of mitochondrial protein synthesis in the CCl4 lesion, work has since concentrated on the action of CAP on earlier events of CCl4 intoxication. CAP, L-CAP and Tevenel showed no effect on the destruction of P-450 in the first 5 hours after CCl4, but CAP (and not Tevenel) was shown to decrease the appearance of lipid dienes in microsomal membranes. Neither L-CAP, CAP or Tevenel was shown to significantly interfere with a lipid peroxidation incubation system composed of microsomes, NADPH, phosphate buffer and Fe ions. The system was easily inhibited by SKF 525A, a P-450 inhibitor. Comparison of SKF 525A with CAP, however, indicated that CAP was a superior mitochondrial protective agent. Current work is proceeding to define the steps that lie between the initial CCl4 lesion in the endoplasmic reticulum and the ultimate mitochondrial dysfunction, and to determine at which point CAP either relieves or negates a CCl4-induced perturbation. BIBLIOGRAPHIC REFERENCES: Brabec, M.J. and Bernstein, I.A., "Modulation of Carbon Tetrachloride-induced Liver Damage by Chloramphenicol," Fed. Proceedings (Abstracts ASBC) 1975.